Genetically engineered mesenchymal stem cells as a proposed therapeutic for Huntington's disease.

There is much interest in the use of mesenchymal stem cells/marrow stromal cells (MSC) to treat neurodegenerative disorders, in particular those that are fatal and difficult to treat, such as Huntington's disease. MSC present a promising tool for cell therapy and are currently being tested in FDA-approved phase I-III clinical trials for many disorders. In preclinical studies of neurodegenerative disorders, MSC have demonstrated efficacy, when used as delivery vehicles for neural growth factors. A number of investigators have examined the potential benefits of innate MSC-secreted trophic support and augmented growth factors to support injured neurons. These include overexpression of brain-derived neurotrophic factor and glial-derived neurotrophic factor, using genetically engineered MSC as a vehicle to deliver the cytokines directly into the microenvironment. Proposed regenerative approaches to neurological diseases using MSC include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation, MSC in the brain promote endogenous neuronal growth, encourage synaptic connection from damaged neurons, decrease apoptosis, reduce levels of free radicals, and regulate inflammation. These abilities are primarily modulated through paracrine actions. Clinical trials for MSC injection into the central nervous system to treat amyotrophic lateral sclerosis, traumatic brain injury, and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of Huntington's disease is discussed

Canadian perspectives in multiple myeloma on the use of steroids in clinical practice based on patient and healthcare provider interviews

Corticosteroid (steroid) medications are associated with challenging adverse effects that can negatively impact patient quality of life. However, owing to a long legacy of effective use in treatment protocols, they remain a cornerstone of multiple myeloma (MM) care. We conducted a roundtable with Canadian healthcare providers (HCPs) with diverse healthcare backgrounds and involvement in MM care as well as with patients with MM. Our goal was to develop clear guidance for steroid management aimed at improving patient quality of life, taking into account patient perspective and experiences with managing the disease. Our recommendations, which are based on the insights acquired from this discussion, can be categorized to the following areas: steroid prescribing, dosing, and modifications; managing adverse effects; and patient-HCP communication. These recommendations can be used by the entire multi-disciplinary hematology team to improve patient quality of life while being treated with steroid medication for multiple myeloma

Clinical trial perspective for adult and juvenile Huntington′s disease using genetically-engineered mesenchymal stem cells

Progress to date from our group and others indicate that using genetically-engineered mesenchymal stem cells (MSC) to secrete brain-derived neurotrophic factor (BDNF) supports our plan to submit an Investigational New Drug application to the Food and Drug Administration for the future planned Phase 1 safety and tolerability trial of MSC/BDNF in patients with Huntington′s disease (HD). There are also potential applications of this approach beyond HD. Our biological delivery system for BDNF sets the precedent for adult stem cell therapy in the brain and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), Alzheimer′s disease, and some forms of Parkinson′s disease. The MSC/BDNF product could also be considered for studies of regeneration in traumatic brain injury, spinal cord and peripheral nerve injury. This work also provides a platform for our future gene editing studies, since we will again use MSCs to deliver the needed molecules into the central nervous system

Clinical trial perspective for adult and juvenile Huntington's disease using genetically-engineered mesenchymal stem cells.

Progress to date from our group and others indicate that using genetically-engineered mesenchymal stem cells (MSC) to secrete brain-derived neurotrophic factor (BDNF) supports our plan to submit an Investigational New Drug application to the Food and Drug Administration for the future planned Phase 1 safety and tolerability trial of MSC/BDNF in patients with Huntington's disease (HD). There are also potential applications of this approach beyond HD. Our biological delivery system for BDNF sets the precedent for adult stem cell therapy in the brain and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), Alzheimer's disease, and some forms of Parkinson's disease. The MSC/BDNF product could also be considered for studies of regeneration in traumatic brain injury, spinal cord and peripheral nerve injury. This work also provides a platform for our future gene editing studies, since we will again use MSCs to deliver the needed molecules into the central nervous system

Developing stem cell therapies for juvenile and adult-onset Huntington's disease.

Stem cell therapies have been explored as a new avenue for the treatment of neurologic disease and damage within the CNS in part due to their native ability to mimic repair mechanisms in the brain. Mesenchymal stem cells have been of particular clinical interest due to their ability to release beneficial neurotrophic factors and their ability to foster a neuroprotective microenviroment. While early stem cell transplantation therapies have been fraught with technical and political concerns as well as limited clinical benefits, mesenchymal stem cell therapies have been shown to be clinically beneficial and derivable from nonembryonic, adult sources. The focus of this review will be on emerging and extant stem cell therapies for juvenile and adult-onset Huntington's disease

Generation of human vascularized brain organoids

The aim of this study was to vascularize brain organoids with a patient's own endothelial cells (ECs). Induced pluripotent stem cells (iPSCs) of one UC Davis patient were grown into whole-brain organoids. Simultaneously, iPSCs from the same patient were differentiated into ECs. On day 34, the organoid was re-embedded in Matrigel with 250 000 ECs. Vascularized organoids were grown in vitro for 3-5 weeks or transplanted into immunodeficient mice on day 54, and animals were perfused on day 68. Coating of brain organoids on day 34 with ECs led to robust vascularization of the organoid after 3-5 weeks in vitro and 2 weeks in vivo. Human CD31-positive blood vessels were found inside and in-between rosettes within the center of the organoid after transplantation. Vascularization of brain organoids with a patient's own iPSC-derived ECs is technically feasible

Developing stem cell therapies for juvenile and adult-onset Huntington's disease.

Stem cell therapies have been explored as a new avenue for the treatment of neurologic disease and damage within the CNS in part due to their native ability to mimic repair mechanisms in the brain. Mesenchymal stem cells have been of particular clinical interest due to their ability to release beneficial neurotrophic factors and their ability to foster a neuroprotective microenviroment. While early stem cell transplantation therapies have been fraught with technical and political concerns as well as limited clinical benefits, mesenchymal stem cell therapies have been shown to be clinically beneficial and derivable from nonembryonic, adult sources. The focus of this review will be on emerging and extant stem cell therapies for juvenile and adult-onset Huntington's disease

A Simple and Interpretable Mortality-Based Value Metric for Condition- or Procedure-Specific Hospital Performance Reporting

Objective: To develop a simple, interpretable value metric (VM) to assess the value of care of hospitals for specific procedures or conditions by operationalizing the value equation: Value = Quality/Cost. Patients and Methods: The present study was conducted on a retrospective cohort from 2015 to 2018 drawn from the 100% US sample of Medicare inpatient claims. The final cohort comprised 637,341 consecutive inpatient encounters with a cancer-related Medicare Severity-Diagnosis Related Grouping and 13,307 consecutive inpatient encounters with the International Classification of Diseases, Ninth Revision or International Classification of Diseases, Tenth Revision procedure code for partial or total gastrectomy. Claims-based demographic and clinical variables were used for risk adjustment, including age, sex, year, dual eligibility, reason for Medicare entitlement, and binary indicators for each of the Elixhauser comorbidities used in the Elixhauser mortality index. Risk-adjusted 30-day mortality and risk-adjusted encounter-specific costs were combined to form the VM, which was calculated as follows: number needed to treat = 1/(Mortalitynational − Mortalityhospital), and VM = number needed to treat × risk-adjusted cost per encounter. Results: Among hospitals with better-than-average 30-day cancer mortality rates, the cost to prevent 1 excess 30-day mortality for an inpatient cancer encounter ranged from $71,000 (best value) to$1.4 billion (worst value), with a median value of $543,000. Among hospitals with better-than-average 30-day gastrectomy mortality rates, the cost to prevent 1 excess 30-day mortality for an inpatient gastrectomy encounter ranged from$710,000 (best value) to $95 million (worst value), with a median value of$1.8 million. Conclusion: This simple VM may have utility for interpretable reporting of hospitals’ value of care for specific conditions or procedures. We found substantial inter- and intrahospital variation in value when defined as the costs of preventing 1 excess cancer or gastrectomy mortality compared with the national average, implying that hospitals with similar quality of care may differ widely in the value of that care